Coronary artery disease is the leading cause of mortality and disability in the US. Current treatment methods including autologous artery and vein grafts have considerable limitations despite decades of refinement. Two critical challenges in small artery substitutes are high compliance and nonthrombogenicity. Our long-term goal is to create mechanically competent, nonthrombogenic and vasoresponsive small artery substitutes. The objective of this proposal is to engineer mechanically competent small arteries. The central hypothesis of this application is that a biomimetic culture environment will facilitate the formation of small arteries with structure and properties representative of the native vessels. We will create a culture condition that mimics angiogenesis and vasculogenesis by cultivating vascular progenitor cells in rationally-designed elastomeric scaffolds under dynamic mechanical conditions. This innovative approach may lead to physiological compliance in the near future, and nonthrombogenicity and vasoresponsiveness ultimately. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims. Under aim 1, we will fabricate tubular scaffolds from elastomeric and stiff biomaterials that will be used in aims 2 and 3 to examine the effects of scaffold properties on the structure and properties of the resultant artificial arteries. The feedbacks from aims 2 and 3 will guide the selection and optimization of the scaffolds. Under aim 2, we will culture circulating endothelial progenitor cells with smooth muscle cells to engineer closely interacting intima/media composites with compliance matching native arteries. Aim 3 will focus on increasing the strength and stability of the constructs by adding an adventitia layer while maintaining the high compliance of the intima/media layer. The combined work in aims 1 to 3 is expected to create mechanically competent small arteries that provides a solid foundation for future investigations in antithrombogenicity and vasoresponsiveness. This multidisciplinary proposal combines the complementary expertise of the Principal Investigator in biomaterial and regenerative medicine, and the Collaborators in vascular cell biology, biomechanics, and blood-material interfacial phenomenon. When successfully completed, the proposed research is expected to represent a significant advance in the field of blood vessel substitutes and accelerate the translation of tissue-engineered arteries from benchside promise to bedside benefit.